Immunopharmacokinetic studies of several biological response modifiers (BRMs) in vivo have been performed. The majority of BRMs (MVE-2, Poly ICLC, IFN, glucan, Lentinan, Picibanil, MnC12, C. parvum, BCG) augment both NK cell and MPhi tumoricidal activity. However, Imuthiol appeared to be selective for NK cells and Picolinic acid appeared selective for MPhi. Multiple treatments with several BRMs maintained high levels of MPhi activity but did not maintain elevated NK activity. Several possible mechanism(s) for this hyporesponsiveness to augmentation of NK cell activity were eliminated, i.e. suppresor lymphocytes or MPhi and PGE production. The hyporesponsiveness to NK boosting by multiple treatments with BRMs was consistantly found to be associated with a decrease in splenic large granular lymphocytes (LGLs), which are associated with NK cell activity, indicating a failure to maintain the expansion of LGLs in the spleen. Several BRMs were also examined in vitro and in vivo for their capacity to induce the production and secretion of regulatory factors (colony stimulating factor, CSF; Prostaglandin E1 and E2, PGE; Interferon, IFN). Poly ICLC, MVE-2, BM41332 and Picibanil induced the secretion of CSF and PGE. Poly ICLC and Picibanil also stimulated IFN secretion. Serum levels of CSF following injection with Poly ICLC or MVE-2 remained significantly elevated for 7 days compared to the 7 minute half-life of exogenously injected CSF. The increased CSF was found to be accompanied by increased bone marrow (BM) cells and stem cells (GM-CFU-C) developing from BM cells. MVE-2 and Poly ICLC treatment following cytoreductive chemotherapy (cyclophosphamide) resulted in an earlier and elevated recovery of depressed NK activity and of bone marrow functon. Extensive studies with the MBL-2 lymphoma show that combined cyclophosphamideand BRM treatment (MVE-2 or Poly ICLC) leads to longer survival and an increased number of long-term survivors. The additive therapeutic effects of BRMs plus chemotherapy appears to be attributable to the ability of BRMs to reconstitute and/or enhance Nk and MPhi tumoricidal activity as well as to reconstitute bone marrow cellularity.